Medicine and Health Sciences Commons^™

Methamphetamine-Induced Dna Double-Stranded Breaks: The Impact Of The Dopamine Transporter And Insights Into The Mechanisms Of Dna Damage In Mouse Neuro 2a Cells, Lizette Couto

Dissertations, Theses, and Capstone Projects

Methamphetamine (METH) abuse remains a global health concern, with emerging evidence highlighting its genotoxic potential. In the central nervous system METH enters dopaminergic cells primarily through the dopamine transporter (DAT), which controls the dynamics of dopamine (DA) neurotransmission by driving the reuptake of extracellular DA into the presynaptic neuronal cell. Additional effects of METH on the storage of DA in synaptic vesicles lead to the dysregulated cytosolic accumulation of DA. Previous studies have shown that after METH disrupts intracellular vesicular stores of DA, the excess DA in the cytosol is rapidly oxidized. This generates an abundance of reactive oxygen species …

Sex Differences In Mood And Anxiety-Related Outcomes In Response To Adolescent Nicotine Exposure, Tsun Hay Jason Ng

Electronic Thesis and Dissertation Repository

Nicotine dependence is causally linked to increased risk of mood/anxiety disorders in later life. Females are reported to experience a higher prevalence of anxiety/depressive disorders and challenges in smoking cessation therapies, suggesting a potential sex-specific response to nicotine exposure and mood/anxiety disorder risk. However, pre-clinical evidence of sex-specific responses to adolescent nicotine exposure is unclear. Thus, to determine any sex differences in anxiety/depressive-related outcomes, adolescent male and female Sprague Dawley rats received nicotine (0.4 mg/kg; 3x daily) or saline injections for 10 consecutive days, followed by behavioural testing, in-vivo electrophysiology and Western Blot analyses. Our results revealed that adolescent nicotine …

A Comparison Of Pm-Nato3’S Influence On Neural Progenitors And Mature Dopamine Neurons, Mary E. West

Masters Theses

This thesis presents significant findings regarding the role of PM-Nato3 in its interaction with developing neurons in the context of Parkinson's disease (PD) and regenerative medicine. We investigated the effects of PM-Nato3 on dopamine (DA) neurogenesis under different culture conditions, both in vitro and in vivo. In the standard dopaminergic culture condition, PM-Nato3 potentially increased the speed of DA neuron production but did not significantly increase the yield of DA neurons. In a minimal culture condition, there was no notable difference between the control and PM-Nato3 conditions, suggesting minimal impact on DA neurogenesis. In vivo studies using a mouse model …

The Impact Of Levodopa Administration On Learning From Short-Term And Long-Term Action Consequences: A Paradigm Validation., Masood Rezaei

Electronic Thesis and Dissertation Repository

Behavioral and neuroimaging studies have identified two valuation systems in the human brain for controlling behavior known as model-free (MF) and model-based (MB). MF is based on immediate evaluation and MB is based on long-term evaluation of the outcome of our decisions. Previous studies suggest that dopamine baseline activity may play an important role in the balance between the two systems and determine how they compete or interact in controlling our actions. The overarching aims of this study is to investigate the impact of levodopa administration on learning from immediate and long-term action consequences, and to dissociate the role of …

The Determination Of Phosphorylation Of Nato3 By Pka, Miranda M. Regenold

Masters Theses

One of the leading regulators of neuronal cell differentiation in the CNS is the family of basic helix–loop–helix (bHLH) transcription factors. One of these proteins, Nato3, is associated with the formation of dopaminergic neurons. Transcription factors can be regulated by kinase activity, and in order to detect the associated change of phosphorylation of Nato3, we have generated Nato3 with specific epitope tags that allow for the detection and isolation of the Nato3 protein. Through subcloning techniques and a successful transformation of the Nato3 gene with the sequences of the 3X-Flag epitope and the Myc epitope into the pcDNA3.0 vector, we …

Behavioral And Neurobiological Evidence Of Epigenetic Transmission In The Neonatal Quinpirole Rodent Model Of Schizophrenia, Wesley Gill

Electronic Theses and Dissertations

Quinpirole is a dopamine D2 receptor agonist that if administered to rats from postnatal day (P)1-21 results in increased dopamine D2 receptor sensitivity throughout the animal’s lifetime. This increase in receptor sensitivity is consistent with schizophrenia. This model has additional consistencies with human schizophrenia, including sensorimotor gating deficits, enhanced behavioral and neurobiological responses to nicotine, and protein alterations consistent with the disorder. In this study, a second generation of the neonatal quinpirole (NQ) rodent model was created to investigate if long term changes caused by NQ treatment would be passed to offspring. NQ treated rats were mated and their offspring …

Activation Of The Sonic Hedgehog Effector Smoothened Counteracts L-Dopa Induced Dyskinesia By Restoring Cholinergic Interneuron Function, Lauren Malave

Dissertations, Theses, and Capstone Projects

Many types of neurons act as multimodal signaling centers. Yet, we have only limited insight into the regulation and functional consequences of neuronal co-transmission. For example, dopamine (DA) neurons, whose degeneration causes motor deficits characteristic of Parkinson’s Diseases (PD), communicate with all their targets by DA but only a selective subset of their targets using GABA, Glutamate, and the secreted cell signaling protein Sonic Hedgehog (Shh). It is unknown whether Levo-dopamine (L-Dopa) induced dyskinesia (LIDs), a severely debilitating side effect of DA supplementation in PD, might appear because DA neuron targets are exposed to high DA- but low Shh- signaling …

Dopamine-Dependent Transcriptional Dynamics In Striatal Physiology And Cocaine Reward, Morgan Elizabeth Zipperly

All ETDs from UAB

Exposure to drugs of abuse alters transcriptional programs and neuronal activity, leading to long-lasting cellular and behavioral adaptations that may contribute to addiction. The nucleus accumbens (NAc), part of the mesocorticolimbic dopamine pathway, plays a central role in motivation, reward, and reward-related learning, and this brain region is highly implicated in the development and maintenance of addiction. However, the specific contributions of defined cell populations in the NAc to drug reward processes is still poorly understood. Here, we used electrophysiological, optogenetic, and single-nucleus RNA-sequencing (snRNA-seq) approaches in a rodent model system to define the acute physiological and transcriptional responses of …

When Brain Stimulation Backfires, Sarah Beth Bell

Theses and Dissertations--Psychology

tDCS brain stimulation does not always work in the intended direction. It has been found to sometimes worsen behavior rather than improve it. A preliminary study shows that people high on sensation-seeking and lack of premeditation were prone to reverse effects of tDCS on performance on a Stop Signal Task. Both of these constructs are related to dopamine levels. Study 2 seeks to intentionally cause a reverse effect of tDCS by increasing participants’ dopamine levels via caffeine. There was not a significant interaction between tDCS and caffeine on errors on the Stop Signal Task in this study. However, other factors …

Transcriptional Dynamics Of Dopaminergic Signaling, Katherine Elizabeth Savell

All ETDs from UAB

Drugs of abuse increase dopamine concentrations in the nucleus accumbens, a key reward structure that integrates contextual and cue-related information and regulates motivated behavior. This surge of dopamine triggers cell signaling cascades that converge in the nucleus to cause changes in gene expression, which are thought to lead to the observed functional and structural alterations in the reward circuit after exposure to drugs of abuse. However, while various drugs of abuse cause transcriptional changes, previously available tools have not had the capacity to deeply characterize these gene programs. Therefore, we optimized a dual lentivirus CRISPR system for targeted gene modulation …

An Interface Of The Taste And Reward Systems In The Brainstem And Its Role In Feeding, Louis Saites

Theses and Dissertations (ETD)

We eat what tastes good. We also eat because it is necessary for our health. In fact, some of the most nutritious foods (e.g., vegetables) are often less appetizing, and the tastiest (e.g., fast food, ice cream) may be the least healthy. Despite the former, we may also have a lower limit of what we accept at which point nutrition becomes irrelevant (e.g., “spinach is just too yucky”). Further, we may eat unhealthily because of overwhelming urges. We investigated the complex interactions of taste and feeding at the neurobiological level using the experiments described.

In one sense, this neurobiology begins …

Possible Breakdown Of Dopamine Receptor Synergism In A Mouse Model Of Huntington's Disease, Samantha F. Kennedy

University of New Orleans Theses and Dissertations

The model of basal ganglia function proposed by Albin, Young and Penney (1989) describes two anatomically independent motor pathways, the direct and indirect. However, under normal conditions striatal dopamine (DA) is required for the expression of motor behavior, and DAergic control of the two pathways (via D1 and D2 receptors, respectively) is dependent on co-activation. We tested for a possible breakdown of D1/D2 synergism using transgenic R6/1 mice bearing the human huntingtin allele (Htt). Motor stereotypy, observed prior to the onset of HD-related symptoms, was rated on a 5-point scale following activation of: A) D1 receptors alone, B) D2 receptors …

Dopamine Levels In The Brain Of Rat Models Of Human Rheumatoid Arthritis, Amelia Stinson

Theses & Dissertations

Research Focus. Rheumatoid arthritis (RA) is a chronic, debilitating, autoimmune disease that causes the destruction of bone tissue and the articular structures of joints. At least 30% of RA patient populations have cognitive impairment. Acidic dopamine (DA) is the principal neuroimmunotransmitter that links the central nervous system and peripheral nervous system together. The aim of the present study was to determine the levels of DA and its two acidic metabolites: 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in arthritic induced rats, and whether their levels vary across four different parts of the brain: amygdala (AMG), front cerebral cortex (CX), hippocampus …

Pitx3null Mutant (Striatal Dopamine-Deficient) Mice Have Exaggerated Spiny Projection Neuron Responses To L-Dopa And D1 Agonism And Lack Baseline Striatonigral Spiking, Ben Sagot

Theses and Dissertations (ETD)

L-3,4 dihidroxyphenylalanine (l-DOPA) strongly stimulates motor activity in parkinsonian patients and animal models of Parkinson's disease. Severe striatal dopamine (DA) loss characterizes Parkinson's disease and its animal models. Given the canonical rate model of Parkinson's Disease pathophysiology based on differences in DA pharmacology manifesting as electrophysiological differences in striatal projection neuron (SPN) spike rates, SPNs should increase spiking during the motor response to l-DOPA. In fact, stimulating specific subsets of these neurons to spike in freely-moving wild type and parkinsonian animals causes or inhibits motor activity as predicted. However, pharmacological effects of DA deficiency, let alone those of DA replacement, …

Transcriptional Dysregulation In Interneurons Causes Altered Modulation Of Hippocampal Synaptic Transmission And Circuit Function By The Dopamine System, Lillian J. Brady

All ETDs from UAB

Genetic deletion of the transcriptional coactivator PGC-1α leads to transcriptional dysregulation in interneurons, and transcriptional dysregulation in interneurons lead to changes in hippocampal synaptic transmission and circuit function. Hippocampal circuit activity and synaptic transmission alterations have implications for symptoms of cognitive impairment in neurological disorders like schizophrenia. Modulation of dopamine receptor activity through pharmacologic application of haloperidol and the specific dopamine D4 receptor antagonist L-745,870 in PGC-1α-/- mice leads to altered effects on inhibitory/excitatory synaptic transmission balance, circuit function, and innate hippocampal dependent nesting behavior. These are key aspects underlying hippocampus dependent cognitive impairment. Specifically, bath application of haloperidol restores …

Conduction States Of The Human Dopamine Transporter, Krasnodara Cameron

Theses and Dissertations

Dysregulation of dopaminergic homeostasis has been established as the primary source of numerous neurological disorders including Parkinson’s and drug addiction. A tonic increase of dopamine (DA) in the nucleus accumbens is required for associating everyday events and behaviors with rewards. Yet many addictive exogenous compounds such as amphetamine (AMPH) and cocaine (COC) produce a much greater augmentation of synaptic DA levels that are linked to euphoria and a shift in behavior towards drug seeking. The protein responsible for maintaining extracellular levels of DA is the dopamine transporter (DAT). It is primarily located in the perisynaptic area at terminals of pre-synaptic …

Synaptic And Neurochemical Profiles Of The Nucleus Accumbens In Postmortem Schizophrenia, Lesley Mccollum

All ETDs from UAB

Schizophrenia is a mental illness affecting 1% of the population worldwide. Treatment options are limited for patients, due in part to the lack of understanding of the pathophysiological mechanisms of schizophrenia. In order to improve treatment, it is vital to gain a better understanding of the underlying pathology of the disorder. One region of particular interest is the nucleus accumbens (NAcc). Part of the ventral striatum, this region is thought to play a role in schizophrenia pathology for multiple reasons: afferent input of many brain regions implicated in schizophrenia is integrated here; the dopamine and glutamate systems, both known to …

The Effect Of Gaba A Antagonism On Locomotor Activity And Dopamine Release In The Mouse Caudate Putamen Following Acute Toluene Inhalation: An In-Vivo Microdialysis Study, Sean Callan

Wayne State University Theses

Toluene is ubiquitous solvent commonly inhaled recreationally. Despite its frequency of misuse, there is little understanding of how toluene acts within the brain. To examine this, this master's thesis examined the impact of acutely inhaled toluene on dopamine (DA) release in the mouse CPu in vivo using microdialysis techniques. Toluene inhalation produced dose-dependent increases in DA levels as well as changes in locomotor activity. These effects were potentiated by pre-treatment with the GABAA antagonist bicuculline via reverse microdialysis delivery. These results suggest that the DA dynamics of toluene abuse are related to toluene's previously explored effects on the GABA system. …

Evaluation Of Presynaptic Dopamine Dynamics After: Toluene Inhalation Or Trkb Receptor Activation, Aaron Kwaku Apawu

Wayne State University Dissertations

Dopamine (DA) neurons in the striatum mediate several functions of the brain and have been linked to a host of neurological disorders including Parkinson's disease and addiction, both of which occur as a result of dysfunction in the DA system. In the present study, our first objective was to understand how the striatal DA system adapts to acute and repeated administration of inhalant toluene. The use of toluene as inhalant, like other drugs of abuse, is known to perturb DA neurotransmission in the brain reward pathway. However, the exact mechanism underling toluene's influence on striatal DA neurotransmission is unknown. The …

Alterations In The Mouse Striatum Following Acute And Repeated Ethanol Exposure, Brooke D. Newman

Wayne State University Dissertations

Brain-derived neurotrophic factor (BDNF) is an important neuromodulator that has implicated in regard to several neurological disorders, including alcohol addiction. BDNF is also an important modulator of dopamine (DA), a neurotransmitter that is heavily implicated in addiction with one of the DA rich brain regions being referred to as the reward center of the brain. One of the focuses in alcohol dependence research includes determining risk factors that make an individual more susceptible to becoming dependent. BDNF has been of interest as a risk factor due to its involvement in ethanol consumption and addiction evidenced in a vast number of …

Determinants Of Abuse-Related Effects Of Monoamine Releasers In Rats, Clayton T. Bauer

Theses and Dissertations

Monoamine releasers constitute a class of compounds that promote release of dopamine, serotonin, and/or norepinephrine. These compounds have a range of different uses in the medical setting, including treatment of attention deficit hyperactivity disorder, narcolepsy, and obesity. A major limitation of many of these compounds (i.e. amphetamine, methamphetamine, phenmetrazine) is their propensity for abuse; however, not all monoamine releasers are abused (i.e. fenfluramine). The goal of this dissertation was to examine pharmacological determinants of abuse-related effects produced by monoamine releasers in two preclinical assays in rats: intracranial self-stimulation (ICSS) and drug discrimination. First, this work confirmed and expanded upon previous …

Striatal Dopamine Dynamics Upon Manganese Accumulation, Madiha Khalid

Wayne State University Dissertations

STRIATAL DOPAMINE DYNAMICS UPON MANGANESE ACCUMULATION

by MADIHA KHALID

August 2013

Advisor: Dr. Tiffany Mathews

Major: Chemistry (Analytical)

Degree: Doctor of Philosophy

Although manganese (Mn) is fundamental for many biological processes, exposure to excess amounts leads to a neurological disorder termed manganism. Due to its symptomatic similarity to Parkinson's disease, as well its preferential accumulation in dopamine rich brain regions, alterations in the dopamine system are implicated in the onset of manganism. In my research, Mn overexposure is mimicked via subcutaneous administration of manganese chloride to C57BL/6 mice over the course of seven days using a protocol that has been …

Sex Differences In The Dopaminergic Regulation Of Courtship, But Not Pairing Behaviors In Zebra Finches, Erin Marie Lowrey

Wayne State University Theses

Dopamine is one of the key ingredients in the glue that cements social bonds in vertebrates. The D2 dopamine receptor has been implicated in the regulation of monogamous pair bonding in the prairie vole. While dopamine affects courtship behaviors in the male zebra finch, the behavioral role of dopamine acting at D2 receptors in both males and females deserves further attention. We hypothesized that the D2 receptor would regulate courtship and pairing behaviors in the male and female zebra finch. Sixteen males and females were tested using a repeated measures design. On day 1, the zebra finches were injected with …

Nigrostriatal Dopamine-Neuron Function From Neurotrophic-Like Peptide Treatment And Neurotrophic Factor Depletion, Ofelia Meagan Littrell

Theses and Dissertations--Neuroscience

Trophic factors have shown great promise in their potential to treat neurological disease. In particular, glial cell line-derived neurotrophic factor (GDNF) has been identified as a potent neurotrophic factor for midbrain dopamine (DA) neurons in the substantia nigra (SN), which lose function in Parkinson’s disease (PD). GDNF progressed to phase II clinical trials, which did not meet proposed endpoints. The large size and binding characteristics of GDNF have been suspected to contribute to some of the shortcomings of GDNF related to delivery to target brain regions. Smaller peptides derived from GDNF (Dopamine-Neuron Stimulating Peptides – DNSPs) have been recently investigated …

D2r Dopamine Receptor Mediates Changes In Dual Specificity Phosphatase Expression In A Small Cell Lung Cancer Cell Line, Scott Lemar Lattimer

Theses and Dissertations (ETD)

Bromocriptine, a D2 dopamine receptor (D2R) agonist, is used clinically as a treatment for pituitary tumors of a lactotroph origin. Many questions remain unanswered about the mechanism of this effect. The antiproliferative effect has not been demonstrated in DMS 53 cell line, a Small Cell Lung Cancer (SCLC). In this thesis, we have shown that treatment with NPA (N‑propylnorapomorphine), a dopamine receptor agonist inhibits ERK phosphorylation and proliferation in DMS 53 cells. NPA treatment causes significant increases in DUSP‑1 (MKP‑1), DUSP‑4 (MKP‑2) and DUSP5 mRNA. NPA treatment also correlates with increases in DUSP5 (hVHR3) protein visualized using Western Blot. These …

Studies Of The Effects Of Dopamine Neuron Stimulating Peptides In Rodent Models Of Normal And Dysfunctional Dopaminergic Systems, Joshua Lee Fuqua

University of Kentucky Doctoral Dissertations

A theoretical post-translational processing model of the proprotein form of glial cell line-derived neurotrophic factor (GDNF) likely produces three biologically active peptides. The three prospective peptides formed are 5, 11, and 17 amino acid peptides, entitled dopamine neuron stimulating peptide -5 (DNSP-5), -11 (DNSP-11), and -17 (DNSP-17), respectively. The DNSPs were hypothesized to increase dopaminergic neuron function because of their relationship to GDNF: a molecule with established neurotrophic actions on dopaminergic neurons. The DNSPs have the potential to provide a therapeutic molecule similar to GDNF, but with increased ease of delivery and improved bioavailability.

Neurochemical effects of DNSPs were examined …

Comparison Of Affective Analgesia And Conditioned Place Preference Following Cholinergic Activation Of, Elena Schifirnet

Wayne State University Dissertations

Activation of the dopaminergic mesolimbic reward circuitry that originates in the ventral tegmental area (VTA) is postulated to preferentially suppress affective reactions to noxious stimuli (affective analgesia, AA). VTA dopamine neurons are activated via cholinergic inputs, and we have observed that microinjections of the acetylcholine agonist carbachol suppressed vocalizations of rats that occur following administration of brief (1 sec) tail-shocks (vocalization afterdischarges = VAD). VADs are a validated rodent model of pain affect. In addition, the capacity of carbachol to support reinforcement appears to be regionally dependent within VTA. Ikemoto and Wise (2002) reported that carbachol was self-administered in the …

Torsina And The Pathophysiology Of Dyt1 Dystonia, Yu Zhao

Theses and Dissertations (ETD)

The goal of my dissertation work was to examine the systems biology of torsinA, a DYT1 dystonia-associated protein, by using rodent model systems. TorsinA is a putative ATPase associated with a variety of cellular activities (AAA+). Deletion of glutamic acid residue 302/303 in TOR1A is causally associated with many cases of early-onset primary dystonia.

In our work, transient forebrain ischemia and sciatic nerve transection were used as central and peripheral neural perturbations, respectively, to gain insight into the in vivo role(s) of torsinA. Moreover, transgenic mouse models that overexpress either human mutant torsinA (hMT) or wild-type torsinA (hWT) were used …